HDACi induce a plethora of molecular and extracellular effects that alone or in combination, result in potent anti‐cancer activities [1]. The drug targets, HDACs, are diverse and exhibit different substrate specificities and biological functions. Despite the rapid expansion of literature in this area, we remain uncertain of the mechanistic hierarchy of the HDACi. For example, while it is clear that HDACi induce apoptosis associated with altered transcription of proteins involved in the intrinsic and extrinsic pathways, other mechanisms are in play, such as those relating to the aggresome/proteasome system. Through hyperacetylation of histone and non‐histone targets, HDACi can induce quite diverse effects on cellular function. These include: (i) altering immune responses through effects on the host and/or target cells; (ii) inducing permanent (i.e. senescence) or temporary (quiescence) cell‐cycle arrest, usually at the G1/S transition; (iii) inhibiting angiogenesis, and (iv) inducing apoptosis and autophagy [20–24]. HDACi not only induce injury to the cell, they also modulate its ability to respond to stressful stimuli. Moreover, it is important to appreciate that the anti‐tumor effect of these drugs is due to targeting not only the tumor cell itself, but also the tumor microenvironment and the immune milieu.
The question is why do TCLs and other hematologic malignancies show a selection pressure for specific patterns of epigenetic modification? It is well recognized that epigenetic modulation is responsible for sustaining the adaptive transcriptional memory for both central and tissue resident memory T cells [25]. Specifically, this provides the means for different T helper subsets to transcribe inducible genes more rapidly [26].
A key clue that the TCLs represent an “epigenetic disease” came from the empiric finding that HDACi exhibit consistent and reproducible activity (e.g., a response rate of approximately 25%) across all TCL subtypes. While only one in four patients can expect to respond to HDACi, the duration of response seen across these drugs is impressive, typically more than one year. Preclinical studies have confirmed that this vulnerability to HDACi can be exploited in combination. Many studies have now established that the HDACi exhibit potent synergy with a host of other drugs known as “active” in TCL, including HMA, pralatrexate, proteasome inhibitors, and aurora A kinase inhibitors, and could serve as a cornerstone for future platform development [27–33].
Cutaneous TCL (CTCL) was the first malignancy for which HDACi were approved. CTCL is a disease where a panoply of epigenetic abnormalities might explain why HDAC inhibition is associated with clinical benefit in this disease [5]. While mutations in DNMT3A, IDH2, TET2, MLL2, KMT2A, KDM6A, CREBBP, and EP300 genes have been well recognized for years, it remains unclear whether any of these genetic factors portend differential response to HDAC inhibitors [3, 6–10].
DNMT3A functions as a DNA methyltransferase catalyzing cytosine methylation of CpG islands in promoters leading to transcriptional silencing. While mutations in DNMT3A have been identified in about 11–33% of patients with PTCL due to missense or nonsense mutations [34, 35], the mutations frequently coexist with mutated TET2, which may ultimately lead to transcriptional repression [36].
The TET2 gene encodes an alpha‐ketoglutarate dependent dioxygenase, which converts 5mC to 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxylcytosine (5caC) [37–39]. Oxidation of 5mC is part of a demethylation pathway that influences transcriptional activation, where hypermethylation leads to silencing of gene expression, while hypomethylation leads to gene expression. The TET family of proteins are also known to be important in T‐cell differentiation, where loss of function mutations lead to TCL with follicular helper cell‐like features [40–42]. Interestingly, TET2 mutations are seen in up to 70% of PTCL patients. Specifically, it is estimated that TET mutation are found in 42–83% of patients with AITL, 28–48.5% of patients with PTCL not otherwise specified (PTCL‐NOS), and 10% of patients with adult T‐cell leukemia/lymphoma (ATLL) [34–36, 40–43]. Patients with PTCL‐NOS who carry the TET2 mutation often present with a follicular helper type of PTCL, a newly described entity that exhibits many similarities with AITL. Moreover, there can be interactions between the various epigenetic modulators. For example, wild‐type DNMTA3 binding occurs when there is less CpG density compared to TET1 binding, which occurs at a relatively higher CpG density. Both affect the polycomb repressive complex 2 (PCR2)‐mediated methylation of lysine 27 of histone H3 (H3K27), which leads to enrichment of trimethylation at H3K27 and ultimately influences gene expression [44].
Mutations in IDH2, especially at the R172 residue, have also been identified. Mutations in IDH2 alter the catalytic reactions of the Krebs cycle. Wild‐type IDH converts isocitrate to α‐ketoglutarate, a key co‐factor in the oxidative demethylase reactions which remove methyl groups from DNA. Mutant IDH2 converts isocitrate to 2‐hydroxyglutarate, which is an oncogenic metabolite that cannot function as an obligatory cofactor of TET catalytic functions [34, 45–51]. Mutations in IDH2 and TET2 reduce 5hmC levels due to global hypermethylation of promoters and 5′‐cytosine‐phosphate‐guanine‐3′ (CpG) islands (i.e. leading to transcriptional repression and gene silencing), likely contributing to peripheral T‐cell lymphomagenesis [49, 50]. While there are only modest data for the role of HMA in TCL, emerging data suggest that they do have marked single‐agent activity in AITL and appear to synergize with HDACi in both preclinical and clinical PTCL experiences [52].
The catalytic subunit of PCR2 is the enhancer of zeste homolog 2
